Endothelin-1 Plasma and Aqueous Humor Levels in Different Types of Glaucoma: A Systematic Review and Meta-Analysis

Background and Objectives: Several studies suggest the complex relationship between Endothelin-1 (ET-1) levels with various types of glaucoma. This systematic review and meta-analysis explore ET-1 levels in plasma and aqueous humor among different types of glaucoma. Materials and Methods: A literature search (PubMed, ScienceDirect, Cochrane Library) was made up to April 2024 (PROSPERO: CRD42023430471). The results were synthesized according to PRISMA Guidelines. Results were presented as standardized mean differences (SMD) with 95% confidence intervals (CI). Results: A total of 2597 subjects (1513 patients with glaucoma vs. 1084 healthy controls) from 23 studies were included in a meta-analysis. Notably, patients with glaucoma reported significantly higher plasma levels of ET-1 compared to controls (SMD: 1.21, 95% CI: 0.59–1.82, p < 0.001). Particularly, plasma ET-1 levels were higher in primary open-angle glaucoma (POAG) (SMD: 0.87, 95% CI: 0.09–1.65, p < 0.05), normal-tension glaucoma (SMD: 0.86, 95% CI: 0.27–1.46, p = 0.05), and angle-closure glaucoma patients (SMD: 1.03, 95% CI: 0.43–1.63, p < 0.001) compared to healthy controls. Moreover, ET-1 aqueous humor levels were significantly higher in patients with glaucoma compared to controls (SMD: 1.60, 95% CI: 1.04–2.15, p < 0.001). In particular, aqueous humor levels were higher in POAG patients (SMD: 2.03 95% CI: 1.00–3.14, p < 0.001), and pseudoexfoliative glaucoma patients (SMD: 2.03, 95% CI: 1.00–3.07, p < 0.001) compared to controls. Conclusions: This meta-analysis indicates that elevated levels of ET-1 plasma and aqueous humor are significantly associated with different types of glaucoma. The pathogenesis of ET-1-related mechanisms may vary across different glaucoma types, indicating that possible therapeutic approaches targeting ET-1 pathways should be tailored to each specific glaucoma type.


Introduction
Glaucoma is a complex disease of ocular disorders causing a characteristic pattern of loss of retinal ganglion cells and damage to their axons, which damage the optic nerve head [1].The global prevalence of glaucoma in the population aged 40 to 80 years is estimated at 3.54%, with a total of 76.0 million in 2020 and 111.8 million in 2040 people worldwide [2].Several risk factors are implicated in glaucoma, such as elevated intraocular pressure (IOP), older age (>60 years old), thinner central cornea thickness, exfoliation syndrome, diabetes, and high blood pressure [3].However, vascular dysregulation has come to light as a critical pathophysiological mechanism involved in glaucoma development and progression [4].
Considerable interest has emerged in Endothelin-1 (ET-1), a potent key modulator of ocular blood flow [5].ET-1 has been characterized as a powerful vasoconstrictor, as it contributes to the basal constrictive tone of systemic vessels and may contribute to autoregulation of ocular blood flow and ocular vessel tone, especially in the choroid and optic nerve head [6,7].ET-1 is a 21 amino acid peptide made by vascular endothelium throughout the body, including tissues relevant to glaucoma (non-pigmented ciliary epithelium, ciliary body muscle, and iris) [8].Several studies have investigated the role of plasma and aqueous humor ET-1 levels, with most of them finding ET-1 plasma concentrations significantly elevated in glaucoma patients, and aqueous humor ET-1 levels to show great heterogeneity between studies and groups [9][10][11].Findings from animal studies are also noteworthy as intravitreal injection of ET-1 in rats resulted in a dose-dependent and sustained reduction of optic nerve head blood flow [12], and ET-1 induced contraction in human trabecular meshwork cell cultures [13].
Although research interest is increasing to shed light on the pathophysiological mechanisms involved in ET-1 levels with the risk of glaucoma disease, the detailed picture of this connection is still obscure, especially among various types of glaucoma.This systematic review and meta-analysis summarizes the existing evidence on the role of ET-1 levels in both plasma and aqueous humor among glaucoma patients compared to healthy controls.In parallel, it also focuses individually on patients with each type of glaucoma, providing an up-to-date, comprehensive view of this relationship.

Literature Search
This study was designed according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) statement [14].The protocol has been prospectively registered in PROSPERO (ID: CRD42023430471).PubMed, Cochrane Library, and Sci-enceDirect databases were searched up to 4 April 2024 for articles examining the role of Endothelin-1 plasma and aqueous humor levels on different types of glaucoma.The following search terms were used with an indicative search query to implement these criteria: "Endothelin-1" or "ET-1".The keywords listed below were used to identify the outcome variables of interest: "Glaucoma", "Primary open-angle Glaucoma", "POAG", "Angle-Closure Glaucoma", "ACG", "Normal Tension Glaucoma", "NTG", "Pseudoexfoliative Glaucoma", or "PEXG".Based on predefined selection criteria, two researchers independently evaluated the articles for eligibility.Any discrepancies were resolved through repeated reviewing and consensus among the authors.Database searches were rerun before final analyses and any appropriate further studies were retrieved for inclusion.

Study Selection and Data Extraction
All original observational studies (cohort, cross-sectional, and case-control) were included based on the following criteria for the included study design: (i) all studies were conducted in human adults (>18 years old); (ii) studies included soluble plasma and/or aqueous humor concentrations of ET-1 in patients with any type of glaucoma and healthy controls; (iii) studies included information about the diagnostic methods and the method of laboratory analysis of ET-1.We excluded from the analysis: (i) all reviews, systematic reviews, and meta-analyses; (ii) non-English language studies; (iii) animal studies; (iv) studies where the levels of ET-1 were unavailable (even after contacting the corresponding author).After the completion of screening, the following information was extracted from the included studies: (i) first author's name; (ii) year of publication and title; (iii) study type/design; (iv) sample size (overall and per group); (v) study location (country); (vi) age and sex for the whole sample and each subgroup included.

Quality Assessment and Publication Bias
The quality assessment and risk of bias assessment for the 23 studies meeting the eligibility criteria were conducted by the Newcastle-Ottawa Quality Assessment Scale (NOS) criteria, adapted for case-control, cross-sectional, and cohort studies respectively [15].NOS assessment is based on three main domains: (i) The selection of participants, (ii) the comparability of the groups, and (iii) the ascertainment of either the exposure or outcome of interest.The maximum score is 9 for case-control and 10 for cross-sectional studies.We assigned scores of 0-3, 4-6, and 7-9 (or 7-10 for cross-sectional design) for low, moderate, and high quality, respectively.Also, publication bias was examined with funnel plot assessment, to evaluate the asymmetry of the values between the two groups under comparison.Outlier studies were removed using Egger's test which is a statistical tool for quantifying funnel plot asymmetry.Study quality was not used as a criterion for outlier removal.

Statistical Analysis
The acquisition of data was achieved through either direct extraction or indirect calculation, following the methodology of Wan et al. formula in order to estimate mean and standard deviation (SD) in the case of data reported as median and interquartile range (IQR) [16].To estimate differences, the standardized mean differences (SMD) of the compared groups and their 95% CIs were estimated using random effect models.The examination of statistical heterogeneity was carried out through Q statistic, based on the χ 2 test (p = 0.05 as the significance threshold) and I 2 was used to quantify the proportion of variance due to between-study heterogeneity.A sensitivity analysis was performed in the analysis of ET-1 levels (both in plasma and aqueous humor) when comparing SMDs between glaucoma patients and control subjects through a leave-oneout strategy.Moreover, a subgroup analysis was conducted between different types of glaucoma and control subjects when the included studies had at least two studies with the same comparison groups.A meta-analysis was conducted using RevMan 5.4 software (The Cochrane Collaboration, Oxford, UK).

Search Results
A total of 281 studies was initially identified with 23 being eligible for inclusion in the systematic review and meta-analysis after the application of exclusion and inclusion criteria (Figure 1).Most of the studies included were case-control (n = 16, 69.6%), and the rest of them were cross-sectional studies (n = 7, 30.4%).There was a total sample size of n = 2597 subjects (1513 patients with glaucoma vs. 1084 healthy controls) (Table 1) .

Quality Assessment
The overall quality was found high for 19 studies (82.6%) and moderate for the remaining 4 (17.3%).Case-control studies displayed an average score of 7.3 out of 9, with 13 (81,3%) being of high quality.The same figure was 7.9 out of 10 for cross-sectional studies  POAG patients, compared to healthy controls, showed an increase of ET-1 plasma levels.
Increased ET-1 levels in POAG patients were related to vascular dysfunction (r = 0.942; p = 0.001) and vascular dysfunction was related to sub-clinical intraocular inflammation (r = 0.968; p = 0.001).

Quality Assessment
The overall quality was found high for 19 studies (82.6%) and moderate for the remaining 4 (17.3%).Case-control studies displayed an average score of 7.3 out of 9, with 13 (81.3%)being of high quality.The same figure was 7.9 out of 10 for cross-sectional studies with 6 of them (85.7%)being of high quality (Supplementary Table S1).From the studies included in the meta-analysis, 17 studies examined plasma ET-1 levels between glaucoma patients and healthy controls.A total of 1743 subjects (1037 glaucoma patients vs. 706 healthy controls) were included in the analysis.The meta-analysis showed significantly higher plasma ET-1 levels for glaucoma patients, by a pooled SMD of 1.21 (95% CI: 0.59-1.82,p < 0.001) (Figure 2, Panel A).Although substantial heterogeneity (I 2 = 96%, p < 0.001) was observed among studies, the sensitivity analysis confirmed the results.It showed higher ET-1 levels for glaucoma patients by a pooled mean difference of 0.42 pg/mL of ET-1 (95% CI: 0.26-0.59,p < 0.001), after funnel plot evaluation and 8 outlier studies removals, with moderate heterogeneity among studies (I 2 = 70%, p < 0.001) (Figure 2, Panel B).

Plasma ET-1 Levels between POAG Patients vs. Healthy Controls
From the studies included in the meta-analysis, 13 studies examined plasma levels between POAG patients and healthy controls, with a total of 1297 subject POAG patients vs. 601 healthy controls).The meta-analysis showed significantly h plasma ET-1 levels in POAG patients, by a pooled SMD of 0.87 (95% CI: 0.09-1.60.03), with a substantial heterogeneity among studies (I 2 = 97%, p < 0.001) (Figure 3,  A).The sensitivity analysis confirmed the results showing higher ET-1 levels for P patients by a pooled mean difference of 0.44 pg/mL ET-1 (95% CI: −0.07-0.95,p < 0

Plasma ET-1 Levels between NTG Patients vs. Healthy Controls
In the present analysis, six studies investigating plasma ET-1 levels between NTG patients and healthy controls were included, with a total of 427 subjects (187 NTG patients vs. 601 healthy controls).The meta-analysis showed significantly higher plasma ET-1 levels in NTG patients, by a pooled SMD of 0.86 (95% CI: 0.27-1.46,p = 0.05), with a substantial heterogeneity among studies (I 2 = 87%, p < 0.001) (Figure 3, Panel C).The sensitivity analysis confirmed the results showing higher ET-1 levels for NTG patients by a pooled MD of 0.39 pg/mL ET-1 (95% CI: 0.19-0.59,p < 0.001), after funnel plot evaluation and one outlier study removal, with a low heterogeneity among studies (I 2 = 48%, p < 0.001) (Figure 3, Panel D).
Plasma ET-1 Levels between PEXG Patients vs. Healthy Controls Among studies included in the meta-analysis, two studies identified exami plasma ET-1 levels between PEXG patients and healthy controls, with a total of 89 sub (36 PEXG patients vs. 53 healthy controls).No significant difference in plasma ET-1 l was observed between the PEXG patients and healthy controls [SMD: 0.31 (95% CI: − 1.31, p = 0.54)] (Figure 4, Panel C).

Aqueous Humor ET-1 Levels between Glaucoma Patients vs. Healthy Controls
From the studies included in the meta-analysis, nine of them examining aqueou mor ET-1 levels between glaucoma patients and healthy controls, with a total of 1166 jects (685 glaucoma patients vs. 481 healthy controls).The meta-analysis showed sig cantly higher aqueous humor ET-1 levels for glaucoma patients, by a pooled SMD of (95% CI: 0.81-3.34,p < 0.001), with a substantial (I 2 = 87%) heterogeneity among stu (Figure 5, Panel A).The sensitivity analysis confirmed the results showing higher aqu humor ET-1 levels for glaucoma patients by a pooled mean difference of 1.98 pg/mL (95% CI: 1.36-2.60,p < 0.001), after funnel plot evaluation and 5 outlier studies remo with moderate heterogeneity among studies (I 2 = 73%, p < 0.001) (Figure 5, Panel B).Plasma ET-1 levels between ACG, PEXG patients, and healthy controls.(A) Forest plot displaying the meta-analysis of plasma ET-1 levels between ACG patients and control subjects, their estimated pooled standardized mean difference (SMD), confidence interval (CI), and study heterogeneity; (B) Forest plot displaying the sensitivity analysis of plasma ET-1 levels between patients with ACG and control subjects, their estimated pooled mean difference (MD), confidence interval (CI), and study heterogeneity; (C) Forest plot displaying the meta-analysis of plasma ET-1 levels between PEXG patients and control subjects, their estimated pooled standardized mean difference (SMD), confidence interval (CI), and study heterogeneity [17,20,21,23].
Plasma ET-1 Levels between PEXG Patients vs. Healthy Controls Among studies included in the meta-analysis, two studies identified examining plasma ET-1 levels between PEXG patients and healthy controls, with a total of 89 subjects (36 PEXG patients vs. 53 healthy controls).No significant difference in plasma ET-1 levels was observed between the PEXG patients and healthy controls [SMD: 0.31 (95% CI: −0.68-1.31,p = 0.54)] (Figure 4, Panel C).

Aqueous Humor ET-1 Levels and Glaucoma Aqueous Humor ET-1 Levels between Glaucoma Patients vs. Healthy Controls
From the studies included in the meta-analysis, nine of them examining aqueous humor ET-1 levels between glaucoma patients and healthy controls, with a total of 1166 subjects (685 glaucoma patients vs. 481 healthy controls).The meta-analysis showed significantly higher aqueous humor ET-1 levels for glaucoma patients, by a pooled SMD of 2.07 (95% CI: 0.81-3.34,p < 0.001), with a substantial (I 2 = 87%) heterogeneity among studies (Figure 5, Panel A).The sensitivity analysis confirmed the results showing higher aqueous humor ET-1 levels for glaucoma patients by a pooled mean difference of 1.98 pg/mL ET-1 (95% CI: 1.36-2.60,p < 0.001), after funnel plot evaluation and 5 outlier studies removals, with moderate heterogeneity among studies (I 2 = 73%, p < 0.001) (Figure 5, Panel B).Forest plot displaying the meta-analysis of aqueous humor ET-1 levels between glaucomatous patients and control subjects, their estimated pooled standardized mean difference (SMD), confidence interval (CI), and study heterogeneity; (B) Forest plot displaying the sensitivity analysis of aqueous humor ET-1 levels between patients with glaucoma and control subjects, their estimated pooled mean difference (MD), confidence interval (CI), and study heterogeneity [17,21,23,25,28,30,33,[36][37][38].

Aqueous Humor ET-1 Levels between POAG Patients vs. Healthy Controls
Five studies were identified investigating aqueous humor ET-1 levels between POAG patients and healthy controls with a total of 900 subjects (531 POAG patients vs. 369 healthy controls).The meta-analysis showed significantly higher aqueous ET-1 levels in POAG patients, by a pooled SMD of 2.70 (95% CI: 0.67-4.73,p < 0.001), with a substantial heterogeneity among studies (I 2 = 99%, p < 0.0001) (Figure 6, Panel A).The sensitivity analysis confirmed the results showing higher aqueous humor ET-1 levels for POAG patients by a pooled mean difference of 1.47 pg/mL ET-1 (95% CI: 1.04-1.90,p = 0.03), after funnel plot evaluation and two outlier studies removals, with moderate heterogeneity among studies (I 2 = 73%, p = 0 < 0.01) (Figure 6, Panel B). (A) Forest plot displaying the meta-analysis of aqueous humor ET-1 levels between POAG patients and control subjects, their estimated pooled standardized mean difference (SMD), confidence interval (CI), and study heterogeneity; (B) Forest plot displaying the sensitivity analysis of aqueous humor ET-1 levels between patients with POAG and control subjects, their estimated pooled mean difference (MD), confidence interval (CI), and study heterogeneity; (C) Forest plot displaying the meta-analysis of aqueous humor ET-1 levels between PEXG patients and control subjects, their estimated pooled standardized mean difference (SMD), confidence interval (CI), and study heterogeneity; (D) Forest plot displaying the sensitivity analysis of aqueous humor ET-1 levels between patients with PEXG and control subjects, their estimated pooled mean difference (MD), confidence interval (CI), and study heterogeneity [17,21,23,25,28,30,33,36,37].

Discussion
This systematic review and meta-analysis have provided a comprehensive evaluation of the role of ET-1 levels in both plasma and aqueous humor among patients with various types of glaucoma compared to healthy controls.Elevated ET-1 has been characterized as a potential causal risk factor for glaucoma development and progression, as several studies in the last two decades have investigated the role of ET-1 levels both in plasma and aqueous humor [30,34,38].However, the absence of concrete data for the exact relationship of ET-1 levels in each type of glaucoma prompted us to elucidate the exact role it serves among different groups since the last systematic review and meta-analysis by Li S. et al. 2016 included only six studies [40].
The significantly elevated levels of ET-1 in the plasma of glaucoma patients observed in our analysis suggest a systemic alteration in vascular regulation among these patients.(A) Forest plot displaying the meta-analysis of aqueous humor ET-1 levels between POAG patients and control subjects, their estimated pooled standardized mean difference (SMD), confidence interval (CI), and study heterogeneity; (B) Forest plot displaying the sensitivity analysis of aqueous humor ET-1 levels between patients with POAG and control subjects, their estimated pooled mean difference (MD), confidence interval (CI), and study heterogeneity; (C) Forest plot displaying the meta-analysis of aqueous humor ET-1 levels between PEXG patients and control subjects, their estimated pooled standardized mean difference (SMD), confidence interval (CI), and study heterogeneity; (D) Forest plot displaying the sensitivity analysis of aqueous humor ET-1 levels between patients with PEXG and control subjects, their estimated pooled mean difference (MD), confidence interval (CI), and study heterogeneity [17,21,23,25,28,30,33,36,37].

Discussion
This systematic review and meta-analysis have provided a comprehensive evaluation of the role of ET-1 levels in both plasma and aqueous humor among patients with various types of glaucoma compared to healthy controls.Elevated ET-1 has been characterized as a potential causal risk factor for glaucoma development and progression, as several studies in the last two decades have investigated the role of ET-1 levels both in plasma and aqueous humor [30,34,38].However, the absence of concrete data for the exact relationship of ET-1 levels in each type of glaucoma prompted us to elucidate the exact role it serves among different groups since the last systematic review and meta-analysis by Li S. et al., 2016 included only six studies [40].
The significantly elevated levels of ET-1 in the plasma of glaucoma patients observed in our analysis suggest a systemic alteration in vascular regulation among these patients.This aligns with the hypothesis that vascular dysregulation, characterized by an imbalance between vasoconstrictors and vasodilators, may play a crucial role in the development and progression of glaucoma [41,42].The substantial heterogeneity observed across studies could be attributed to variations in study populations, methodologies, and definitions of glaucoma, which highlights the complexity of this disease and the multifactorial nature of its vascular components [4,43,44].Interestingly, our findings also revealed significantly higher levels of ET-1 in the aqueous humor of glaucoma patients.This suggests a localized effect of ET-1 within the ocular environment, which may contribute to the impaired ocular blood flow and increased IOP observed in glaucoma patients [45][46][47][48].The role of ET-1 in regulating ocular blood flow and vessel tone, particularly in the choroid and optic nerve head, provides a plausible mechanism by which elevated ET-1 levels may exacerbate glaucomatous damage [33,[49][50][51].
Understanding the complexities of trabecular meshwork and its pivotal role in regulating IOP in various glaucoma subtypes is crucial for developing targeted therapies [52].Several factors such as changes in extracellular matrix metabolism and antioxidant defense system are known to impair aqueous humor outflow [53].Interestingly, the intravitreal delivery of ET-1 into rat eyes reduced Electroretinography response indicating impaired retinal function and the subsequent decreased blood flow to the retina [54].Another study supported that mitochondrial dysfunction is a significant contributor to ET-1-induced damage of retinal ganglion cells in the context of POAG, since ET-1 downregulated mitochondrial electron transport chain components, underlining the key mechanism behind the neurodegenerative changes observed in POAG [55].Moreover, excessive ET-1 in the aqueous humor can lead to abnormal accumulation of extracellular matrix in trabecular meshwork cultured human cells that restricts aqueous humor outflow, thereby increasing IOP [56].Such tissue-engineered cultures can replicate the morphology and gene expression patterns of specific ocular regions, such as the trabecular meshwork and Schlemm's canal, providing physiologically relevant models for studying the disease and testing treatments [57].Recent treatment studies have shed light on these complex interactions and mechanisms within the trabecular meshwork.Particularly, oral administration of macitentan, a dual endothelin receptor antagonist, effectively attenuated the vasoconstriction caused by intravitreal ET-1 and reduced ET-1 induced retinal ganglion cell loss in rats treated with macitentan.Furthermore, intravitreal injection of Magnesium Acetyltaurate (MgAT) provided significant neuroprotective effects against ET-1 induced damage in the retina by suppressing the neuroinflammatory reaction and offering a way to protect against glaucoma-related retinal damage and preserve vision by addressing both vascular dysfunction and oxidative stress [58,59].Finally, there is a clear need to extend the development of targeted therapies beyond animal models to include human clinical trials, ensuring that treatments addressing ET-1's role in glaucoma can be effectively translated into therapeutic options that mitigate disease progression.
The analysis across different types of glaucoma revealed that elevated ET-1 levels were not uniform across all forms.Notably, significant elevations were observed in POAG, NTG, and ACG patients, but not in PEXG plasma ET-1 levels compared to healthy controls.This may indicate that the pathophysiological mechanisms involving ET-1 may vary among different types of glaucoma, suggesting the need for type-specific therapeutic approaches.Moreover, the heterogeneity observed in our analyses, particularly in the aqueous humor ET-1 levels, underscores the complexity of glaucoma as a group of diseases and the intricate role of vascular factors in its pathogenesis [43].The findings of this meta-analysis can be better understood within its limitations, since the considerable heterogeneity among studies indicates differences in studies' population and the research environment of each work.Future studies should aim to elucidate the mechanisms by which ET-1 contributes to the vascular dysregulation in glaucoma and explore potential therapeutic interventions targeting ET-1 signaling pathways.

Conclusions
This systematic review and meta-analysis demonstrate that elevated levels of ET-1 in both plasma and aqueous humor are significantly associated with glaucoma, supporting the hypothesis that vascular dysregulation plays a crucial role in its pathogenesis.The findings indicate that ET-1's impact varies across different types of glaucoma, suggesting the necessity for type-specific research and treatment strategies.Ultimately, understanding the role of ET-1 in glaucoma could lead to novel approaches to treatment and improve outcomes for patients with this challenging ocular disease.

Medicina 2024 ,Figure 3 .
Figure3.Plasma ET-1 levels between POAG, NTG patients, and healthy controls.(A) Forest p displaying the meta-analysis of plasma ET-1 levels between POAG patients and control subjec their estimated pooled standardized mean difference (SMD), confidence interval (CI), and stu heterogeneity; (B) Forest plot displaying the sensitivity analysis of plasma ET-1 levels between p tients with POAG and control subjects, their estimated pooled mean difference (MD), confiden interval (CI), and study heterogeneity; (C) Forest plot displaying the meta-analysis of plasma ET levels between NTG patients and control subjects, their estimated pooled standardized mean diff ence (SMD), confidence interval (CI), and study heterogeneity; (D) Forest plot displaying the sen tivity analysis of plasma ET-1 levels between patients with NTG and control subjects, their estima pooled mean difference (MD), confidence interval (CI), and study heterogeneity[19-24,26,27,29,3  35,39].

Figure 3 .
Figure3.Plasma ET-1 levels between POAG, NTG patients, and healthy controls.(A) Forest plot displaying the meta-analysis of plasma ET-1 levels between POAG patients and control subjects, their estimated pooled standardized mean difference (SMD), confidence interval (CI), and study heterogeneity; (B) Forest plot displaying the sensitivity analysis of plasma ET-1 levels between patients with POAG and control subjects, their estimated pooled mean difference (MD), confidence interval (CI), and study heterogeneity; (C) Forest plot displaying the meta-analysis of plasma ET-1 levels between NTG patients and control subjects, their estimated pooled standardized mean difference (SMD), confidence interval (CI), and study heterogeneity; (D) Forest plot displaying the sensitivity analysis of plasma ET-1 levels between patients with NTG and control subjects, their estimated pooled mean difference (MD), confidence interval (CI), and study heterogeneity[19- 24,26,27,29,31-35,39].

Figure 4 .
Figure 4. Plasma ET-1 levels between ACG, PEXG patients, and healthy controls.(A) Fores displaying the meta-analysis of plasma ET-1 levels between ACG patients and control subjects estimated pooled standardized mean difference (SMD), confidence interval (CI), and study he geneity; (B) Forest plot displaying the sensitivity analysis of plasma ET-1 levels between pa with ACG and control subjects, their estimated pooled mean difference (MD), confidence in (CI), and study heterogeneity; (C) Forest plot displaying the meta-analysis of plasma ET-1 between PEXG patients and control subjects, their estimated pooled standardized mean diffe (SMD), confidence interval (CI), and study heterogeneity[17,20,21,23].

Figure 4 .
Figure 4. Plasma ET-1 levels between ACG, PEXG patients, and healthy controls.(A) Forest plot displaying the meta-analysis of plasma ET-1 levels between ACG patients and control subjects, their estimated pooled standardized mean difference (SMD), confidence interval (CI), and study heterogeneity; (B) Forest plot displaying the sensitivity analysis of plasma ET-1 levels between patients with ACG and control subjects, their estimated pooled mean difference (MD), confidence interval (CI), and study heterogeneity; (C) Forest plot displaying the meta-analysis of plasma ET-1 levels between PEXG patients and control subjects, their estimated pooled standardized mean difference (SMD), confidence interval (CI), and study heterogeneity[17,20,21,23].

Figure 6 .
Figure 6.Aqueous humor ET-1 levels between patients with POAG, PEXG, and healthy controls.(A)Forest plot displaying the meta-analysis of aqueous humor ET-1 levels between POAG patients and control subjects, their estimated pooled standardized mean difference (SMD), confidence interval (CI), and study heterogeneity; (B) Forest plot displaying the sensitivity analysis of aqueous humor ET-1 levels between patients with POAG and control subjects, their estimated pooled mean difference (MD), confidence interval (CI), and study heterogeneity; (C) Forest plot displaying the meta-analysis of aqueous humor ET-1 levels between PEXG patients and control subjects, their estimated pooled standardized mean difference (SMD), confidence interval (CI), and study heterogeneity; (D) Forest plot displaying the sensitivity analysis of aqueous humor ET-1 levels between patients with PEXG and control subjects, their estimated pooled mean difference (MD), confidence interval (CI), and study heterogeneity[17,21,23,25,28,30,33,36,37].

Figure 6 .
Figure 6.Aqueous humor ET-1 levels between patients with POAG, PEXG, and healthy controls.(A)Forest plot displaying the meta-analysis of aqueous humor ET-1 levels between POAG patients and control subjects, their estimated pooled standardized mean difference (SMD), confidence interval (CI), and study heterogeneity; (B) Forest plot displaying the sensitivity analysis of aqueous humor ET-1 levels between patients with POAG and control subjects, their estimated pooled mean difference (MD), confidence interval (CI), and study heterogeneity; (C) Forest plot displaying the meta-analysis of aqueous humor ET-1 levels between PEXG patients and control subjects, their estimated pooled standardized mean difference (SMD), confidence interval (CI), and study heterogeneity; (D) Forest plot displaying the sensitivity analysis of aqueous humor ET-1 levels between patients with PEXG and control subjects, their estimated pooled mean difference (MD), confidence interval (CI), and study heterogeneity[17,21,23,25,28,30,33,36,37].

Table 1 .
Characteristics of the included studies.
Mean ET-1 levels were significantly higher in all 3 of the glaucoma groups (POAG, NTG, CCAG) than in the control group, there was no significant difference in ET-1 level among the 3 glaucoma groups.Plasma levels of ET-1 were significantly higher in the POAG group in comparison with NTG group and controls.NTG patients showed higher ET-1 levels than the healthy controls, but the differences were not statistically significant.